Effect of thyroid hormone analogs on the activity of choline acetyltransferase in cultures of dissociated septal cells

Thyroid hormones influence the expression of transmitter-specific enzymes by central cholinergic neurons. Based on the fact that these cholinergic neurons degenerate selectively in human Alzheimer's disease, it was hypothesized that thyroid hormones might be beneficial in its treatment. However, since thyroid hormones influence the function of most peripheral organs, derivatives selective for central cholinergic neurons are necessary. The structural requirements of the receptor mediating the effects of the thyroid hormones on central cholinergic neurons were therefore compared with those of the receptors mediating actions on peripheral organs. Cultures were prepared of dissociated neurons from the septal area of fetal rat brains, and the differentiation of cholinergic neurons was assessed by measuring the activity of choline acetyltransferase (ChAT). Triiodothyronine (T3) was found to stimulate ChAT activity in a dose-dependent manner. The effect of T3 was additive to that of nerve growth factor. The potency of derivatives of T3 in elevating ChAT activity in the cultures was compared with their known anti-goiter activity determined in vivo and their binding affinity to the hepatic nuclear receptor measured in vitro. The findings indicate that the structural requirements of central and peripheral receptors are similar and that it therefore appears unlikely that analogs of thyroid hormones can be developed which selectively affect cholinergic neurons.